CN108582765A - A kind of drug 3 D-printing device of precision - Google Patents

Abstract

There is provided herein by increasing material manufacturing come deposition materials or produce such as pharmaceutical dosage form product device and system.The method using these device and system is further provided, and the method that the product of such as pharmaceutical dosage form is produced by increasing material manufacturing.In some embodiments, which includes the material flows system for melting pressurised material, for the pressure sensor of material pressure in detection device, and can be in the control switch including needle seal that open position and closed position switch.The needle seal extends through the feeder channel comprising material and includes tapered end, and wherein the cone-shaped inner surface of the tapered end engagement nozzle of needle seal when needle seal is closed to prevent material from flowing through nozzle.

Description

A kind of drug 3 D-printing device of precision

Technical field

The present invention relates to a kind of systems and device for increasing material manufacturing, and use the method for this device.Especially The method for producing product (such as pharmaceutical dosage form) by increasing material manufacturing.

Background technology

Increasing material manufacturing, also referred to as 3 D-printing allow computer model being molded by squeezing out the material of melting.It is logical A kind of computer system control three-dimensional printer, and control material flowing and the movement of printing nozzle are crossed, needed for formation Shape.In wire rod melts manufacturing process (also referred to as fused glass pellet), material is squeezed into heating head in the form of wire rod, institute Heating head is stated by material molten and is molded on a surface.The surface or the heating head are movable to extrusion molten material Expect into the shape of computer system settings.Other increasing material manufacturing methods have using non-linear shape material, are melted and are pressurizeed, then It is squeezed out by printing nozzle, but these methods often occur that undesirable leakage occurs from printing nozzle, especially when molten When melting material has viscosity.

Latest development in increasing material manufacturing has allowed for using a large amount of different 3 D-printing techniques and uses many differences Material.For example, bio-inert material can be used for producing implantable medical device or customize the increasing material manufacturing work of laboratory consumptive material Skill.See, e.g., Poh et al., Polylactides in Additive Biomanufacturing, Advanced Drug Delivery Reviews,vol.107,pp.228-246(2016).In increasing material manufacturing skill of the exploitation for drug manufacture Progress is also achieved in terms of art.Referring to Goyanes et al., 3D Printing of Medicines:Engineering Novel Oral Devices with Unique Design and Drug Release Characteristics, Molecular Pharmaceutics,vol.12,no.11,pp.4077-4084(2015)。

It is limited however, current increases material manufacturing technology is squeezed out precision by three-dimensional printer material.Drug needs careful Control, the shape of product to ensure manufacture is consistent, and includes accurate and accurate drug dose.There is still a need for exploitations for increasing The accurate system of manufacture process includes the manufacture for drug.

All public publications, patent, patent application and disclosed patent application are included into the present invention as ginseng herein It examines.

Invention content

It is used for through increasing material manufacturing come the device of deposition materials the present invention provides a kind of, including：For melting and applying The feed block of pressure, the feed block include the feeder channel for being connected to print head, and the print head includes nozzle, the spray Mouth includes cone-shaped inner surface and the extrusion for printed material；Pressure sensor, the pressure sensor are described for detecting In nozzle or the nozzle nearby in feeder channel material pressure；And control switch comprising can be in open position and pass The needle seal of closed position switching, the needle seal extend through a part for the feeder channel and include tapered end；Its Described in the tapering point of needle seal engaged with the cone-shaped inner surface of the nozzle, to prevent material from being in described in the needle seal The nozzle is flowed through when closed position.

In some embodiments, the material is non-wire rod.In some embodiments, the material is from described device There is about 100Pas or higher viscosity when middle extrusion.In some embodiments, the material is being squeezed out from described device When have about 400Pas or higher viscosity.In some embodiments, the material melts at a temperature of about 50 DEG C to 400 DEG C Melt.In some embodiments, material squeezes out at a temperature of about 50 DEG C to about 400 DEG C from nozzle.In some embodiments, material Material squeezes out at a temperature of about 90 DEG C to 300 DEG C from nozzle.

In some embodiments, any part of the needle seal of contact material does not have protrusion.

In some embodiments, pressure sensor is connected to the computer system of control feed block to respond the pressure The pressure of sensor report, and the material is pressurized to required pressure.In some embodiments, the pressure of material is in required pressure In the 0.05MPa of power.In some embodiments, the feed block include piston and be connected to it is described charging runner cylinder, Wherein, the piston is actuated to control the pressure of material in the cylinder.In some embodiments, it is driven using stepper motor Piston.

In some embodiments, the tapered end of needle seal includes tip.In some embodiments, the tapering point of needle seal It is conical butt.In some embodiments, the cone-shaped inner surface of nozzle has the tapering point of the first cone angle and needle seal With the second cone angle；And second cone angle is with first cone angle identical or less than first cone angle.In some implementations In example, the second cone angle is about 60 ° or smaller.In some embodiments, the second cone angle is about 45 ° or smaller.In some embodiments In, the ratio of the first cone angle and the second cone angle is about 1：1 to 4：1.

In some embodiments, the extrusion has the diameter of about 0.1mm to 1mm.In some embodiments, the cone Shape end maximum gauge about 0.2mm to about 3.0mm.In some embodiments, there is the extrusion diameter, the tapering point to have Maximum gauge, the maximum gauge of the tapering point and the diameter ratio of the extrusion are about 1：0.8 to about 1：0.1.

In some embodiments, the control switch includes actuator, and needle seal can be located in by the actuator to be beaten Open position or closed position.In some embodiments, the actuator is pneumatic actuator.In some embodiments, the cause Dynamic device is mechanical actuator.

In some embodiments, needle seal passes through the washer being fixed on relative to nozzle location, wherein the washer is closed Feeder channel.

In some embodiments, the feed block includes one or more heaters for melted material.At some In embodiment, the feed block includes one or more temperature sensors, and the temperature sensor is for detecting melted material Temperature.In some embodiments, one or more of temperature sensors are connected to a computer system, the computer System controls corresponding one or more heaters according to the temperature of one or more of temperature sensor monitors.

In some embodiments, the tapered end of the needle seal or the cone-shaped inner surface of nozzle include flexible liner or lining Set.

In some embodiments, described device further comprises that a computer system, the computer system include one A or multiple processors and computer-readable memory, wherein the computer system be used to control the equipment.At some In embodiment, computer-readable memory storage controls the instruction of the device printed product.In some embodiments, computer can It reads memory and stores the pressure that is detected for response pressure sensor to control the instruction of material pressure.In some embodiments In, computer-readable memory is stored controls the finger of the temperature of material for responding the temperature that temperature sensor detects It enables.

In some embodiments, the increasing material manufacturing system includes multiple above-mentioned apparatuses, wherein each feed block is matched It is equipped with control switch.In some embodiments, the system comprises be mounted with the first material first device and be mounted with second The second device of material, wherein first material and the second material are different.In some embodiments, the system comprises calculating Machine system, the computer system includes one or more processors and computer-readable memory, wherein the department of computer science System be used to control the system.In some embodiments, computer-readable memory is stored for being produced using the system print The instruction of product.In some embodiments, computer-readable memory is stored for responding by the pressure in corresponding feed block The pressure that sensor detects controls the instruction of the pressure of the material in each feed block.In some embodiments, it calculates Machine readable memory stores each to control for responding the temperature detected by the temperature sensor in corresponding feed block The instruction of the temperature of material in feed block.

On the other hand, the present invention provides a kind of method producing product with increasing material manufacturing, including：Melted material and give material Pressurization；For the material of flowing by extrusion nozzle, the nozzle includes a cone-shaped inner surface；In nozzle or close to the position of nozzle Set the pressure of monitoring material；The tapering point for making needle seal is engaged with the cone-shaped inner surface of nozzle, to close extrusion to prevent The flowing of melted material；The tapered end of pumpback needle seal, the flowing for passing through extrusion to restorer.In some embodiments In, this method includes the instruction received for manufacturing the product.

On the other hand, the present invention provides a kind of methods producing pharmaceutical dosage form by increasing material manufacturing, including：By medicinal material Material is melted and is pressurizeed；Monitor nozzle in or nozzle nearby material pressure；Material is set to flow through the extrusion of nozzle, the nozzle packet Include cone-shaped inner surface；The tapering point for making needle seal is engaged with the cone-shaped inner surface of nozzle, to close extrusion to prevent to melt The flowing of material；The tapered end of pumpback needle seal, the flowing for passing through extrusion to restorer.In some embodiments, Medicinal acceptable material includes drug.In some embodiments, pharmaceutical dosage form has the targeted release profile of drug.At some In embodiment, this method includes the instruction received for manufacturing pharmaceutical dosage form.

In some embodiments of the above method, the pressure of material keeps approximately constant in nozzle.In some embodiments, This method controls the pressure of material based on the pressure monitored using reponse system.

In some embodiments of the above method, material is non-wire rod.In some embodiments, material has about 100Pas or higher viscosity.

In some embodiments of the above method, any part of the needle seal of contact material is all without protrusion.

In some embodiments of the above method, the temperature of the material in nozzle keeps approximately constant.In some embodiments In, the method includes monitoring the temperature of material.In some embodiments, the method includes temperature based on monitoring to use instead Feedback system controls the temperature of material.

In some embodiments of the above method, the tapered end of needle seal includes sharp tip.In some embodiments, The tapering point of needle seal is conical butt.In some embodiments, the cone-shaped inner surface of nozzle have the first cone angle and The tapering point of needle seal has the second cone angle；Wherein described second cone angle is equal to or less than first cone angle.In some implementations In example, the second cone angle is about 60 ° or smaller.In some embodiments, the second cone angle is about 45 ° or smaller.In some embodiments In, the ratio of the first cone angle and the second cone angle is about 1：1 to 4：1.In some embodiments, extrusion has about 0.1mm to 1mm Diameter.In some embodiments, tapered end has about 0.2 to about 3.0mm maximum gauge.In some embodiments, it squeezes Outlet with diameter and tapered end with maximum gauge, and the ratio of the diameter of the maximum gauge and extrusion of tapered end Rate is about 1：0.8 to about 1：0.1.

On the other hand, a kind of method that product is manufactured by increasing material manufacturing is provided, including：It melts and first material that pressurizes Material；First material is set to flow through the first extrusion of the first jet including cone-shaped inner surface；By the taper of the first needle seal End is engaged with the cone-shaped inner surface of first jet, to close the first extrusion and prevent the flowing of the first material of melting；It is molten Melt and second material that pressurizes；From the tapered end of the second needle seal of cone-shaped inner surface pumpback of second nozzle, to start to make Two materials flow through the second extrusion.In some embodiments, this method includes the instruction received for manufacturing product.

On the other hand, a kind of method that pharmaceutical dosage form is produced by increasing material manufacturing is provided, including by the first medicinal materials It melts and pressurizes；The first medicinal materials are made to flow through the first extrusion of the first jet including cone-shaped inner surface；By the first sealing The tapering point of needle is engaged with the cone-shaped inner surface of first jet, to which the first extrusion of sealing is to prevent the first material melted Flowing；Second medicinal materials are melted and pressurizeed；From the tapered end of the second needle seal of cone-shaped inner surface pumpback of second nozzle, To make the second medicinal materials flow through the second extrusion.In some embodiments, the first medicinal materials or the second medicinal materials are Solvable corrosion material.In some embodiments, the first medicinal materials or the second medicinal materials include drug.In some embodiments, Pharmaceutical dosage form has specified drug release patterns.In some embodiments, this method further includes receiving for manufacturing drug agent The control instruction of type.

In some embodiments of the above method, this method further comprises monitoring in first jet or near first jet The first material pressure；Or the pressure of the second material in monitoring second nozzle or near second nozzle.In some embodiments In, the pressure of the pressure of the first material in first jet or the second material in second nozzle keeps approximately constant.At some In embodiment, this method includes the pressure that pressure based on monitoring controls the first material or the second material using reponse system.

In some embodiments of the above method, the first material or the second material are non-wire rods.

In some embodiments of the above method, any part or the contact second of the first needle seal of the first material are contacted Any part of second needle seal of material does not have protrusion.

In some embodiments of the above method, the temperature of the first material in first jet or second in second nozzle The temperature of material keeps approximately constant.In some embodiments, this method includes monitoring the temperature or the second material of the first material Temperature.In some embodiments, this method includes that the temperature based on the first material monitored is controlled using reponse system The temperature of first material, or the temperature based on the second material monitored control the temperature of the second material using reponse system Degree.

In some embodiments of the above method, the tapering point of the tapering point of the first needle seal or the second needle seal includes point Head.In some embodiments of the above method, the tapered end of the tapered end of the first needle seal or the second needle seal is butt Cone.

In some embodiments of the above method, the cone-shaped inner surface of first jet has the first cone angle and the first sealing The tapering point of needle has the second cone angle；Wherein described second cone angle is equal to or less than first cone angle；Or the second nozzle Tapering point of the cone-shaped inner surface with third cone angle and second needle seal with the 4th cone angle；Wherein described 4th cone Angle is equal to or less than the third cone angle with the 4th cone angle.In some embodiments, the 4th cone angle is about 60 ° or smaller. In some embodiments of the above method, the second cone angle or the 4th cone angle are about 45 ° or smaller.In some implementations of the above method In example, the ratio or the ratio of third cone angle and the 4th cone angle of the first cone angle and the second cone angle are about 1：1 to about 4：1.Above-mentioned In some embodiments of method, the diameter of the first extrusion or the second extrusion with about 0.1mm to about 1mm.In the above method Some embodiments in, the tapering point of the tapering point of the first needle seal or the second needle seal has about 0.2 to about 3.0mm maximum Diameter.

In some embodiments of the above method, the first material or the second material are viscous with about 100Pas or higher Degree.

In some embodiments of the above method, product or pharmaceutical dosage form manufacture in batch mode.The one of the above method In a little embodiments, product or pharmaceutical dosage form manufacture in a continuous mode.

The present invention also provides according to a kind of any of the above described product or pharmaceutical dosage form prepared by method.

Description of the drawings

Fig. 1 shows the present invention by increasing material manufacturing come the exemplary embodiment of the device of printed material.

Fig. 2A shows cross-sectional view of the present invention by the exemplary means of increasing material manufacturing printed material.Fig. 2 B are shown The enlarged view of the print head of Fig. 1 shown devices.As shown in Figure 2 A, needle seal inner surface in the closed position and with nozzle connects It closes.

Fig. 3 A show the tapering point for having acuminous needle seal.Fig. 3 B show the needle seal with frustoconical shape tip Tapered end.Fig. 3 C show the taper of inner nozzle surface.

Fig. 4 shows needle seal and is connected to needle seal to drive the explosion of the component of the pneumatic actuator of needle seal Figure.

Fig. 5 A show that the longitdinal cross-section diagram of the device, Fig. 5 B show the viewgraph of cross-section of the device at plane " A-A ", Fig. 5 C show the side view of the device.

Fig. 6 shows another exemplary embodiment of equipment of the present invention.

Fig. 7 shows that a part for the exemplary means including three feed blocks, each feed block have different Print head.

Specific implementation mode

This application involves a kind of by increasing material manufacturing come the device of deposition materials.The device includes feed block, the confession Material module can be melted and be pressurizeed to material, and the material is selectively included drug.In certain embodiments, the material It is non-filamentary material.The feed block includes a feeder channel for being connected to nozzle.It in feeder channel or can supply Expect that passage upstream is pressurized and/or melting, the material of melting flow through feeder channel and printed by nozzle.The present invention into One step provides a kind of system manufacturing product by increasing material manufacturing comprising two or more devices, each device packet It includes feed block and control switchs.Invention further describes the methods for using this device, and are produced and produced by increasing material manufacturing The method of product and the method that pharmaceutical dosage form is produced by increasing material manufacturing.

When manufacture product, when especially producing drug products, it is desirable to accurately control by the amount of nozzle print material.It is existing One significant problem of the device for increasing material manufacturing is accidental release of the material by nozzle, this can cause printing to be more than required The material of amount.When using two or more nozzles, problem can be more complicated, these nozzles may print different materials, It needs alternately to open or close switch.For example, if when second nozzle prints the second material, first jet leaks the first material Material, then will appear manufacturing defect or waste of material.Due to device and system of the present invention can handle it is a series of have height The drug material of accuracy and high-precision material deposition, so these device and system, which are very suitable for manufacture, has complex geometry The pharmaceutical dosage form of shape and composition.The device that the present invention describes, system and method additionally aid personalised drug, including personalization Dosage and/or personalized release profiles.Personalised drug refers to being layered patients to help based on biomarker Treatment decsion and personalized dosage form design.Personalised drug dosage form allows to adjust drug dose according to the quality of patient and metabolism And release profiles.The pharmaceutical dosage form of the device manufacturing described using the present invention may insure the correct dose of children growth and permit Perhaps the personalised dosage administration of high potency drugs.Personalized dosage form can also by the pharmaceutical composition of all patients at single daily dose, So as to improve patient to the compliance and curative compliance of drug.Modification Digital Design is easier than modification physical equipment.Moreover, The small-sized three-dimensional printing of automation may have insignificant operating cost.Therefore, it is filled using the increasing material manufacturing that the present invention describes Setting can be such that multiple small, personalized batches are economically feasible, and can realize the individual character agent for being intended to improve compliance Type.

In certain embodiments, the customization pharmaceutical dosage form design with specific release profiles is received by computer system, should Computer system is for controlling device of the present invention or system.The computer system can will be used to manufacture with specific The instruction of the pharmaceutical dosage form of release profiles is transferred to the system or equipment, then the production of system or equipment manufacture customization Product.

The present invention provides a kind of more accurate systems, for by accurately controlling the feeder channel near nozzle or nozzle In pressure with increasing material manufacturing come deposition materials or manufacture product (such as pharmaceutical dosage form), and using when needle seal be in close When position, the control switch with needle seal prevents material from flowing through nozzle.Nozzle includes cone-shaped inner surface, and needle seal includes Tapered end, the tapered end are engaged with the cone-shaped inner surface of nozzle to limit material leakage.Needle seal is preferably sharp, matter is thin and does not have There are protrusion, protrusion material may be released nozzle at closed position.The pressure of material preferably keeps approximately constant in a device, The pressure of material can be controlled by monitoring pressure and applying pressure to material using reponse system.Once in this way, needle seal Open position is located in without increasing pressure, so that it may with constant rate of speed extruded material immediately.Essence further can be achieved in this True printed material, this, which can be realized, accurately and precisely manufactures pharmaceutical dosage unit, such as tablet.

In some embodiments, the present invention provides one kind by increasing material manufacturing come deposition materials or manufacture product (such as Pharmaceutical dosage form) device, including：For melting and the feed block of pressurised material, the feed block include feeder channel and Print head, the feeder channel are connected with the print head, and the print head includes nozzle, and the nozzle includes cone-shaped inner surface With the extrusion that be used to print the material；Pressure sensor, the pressure sensor is for detecting the print head or institute State the pressure of the material in the feeder channel near print head；Control switch, control switch includes can be in open position and pass The needle seal of closed position switching, the needle seal extend through a part for the feeder channel and include tapered end；Its Described in the tapering point of needle seal engaged with the cone-shaped inner surface of the nozzle, to be in the closing in the needle seal Material is prevented to flow through the nozzle when position.

Fig. 1 show it is provided by the invention by increasing material manufacturing come deposition materials or manufacture product equipment exemplary reality Apply example.The device includes feed block 102, is used for melting and pressurised material.The material of melting and pressurization flows through feeder channel, The feeder channel is connected to nozzle 104.Pressure sensor 106 is located near the end of nozzle and feeder channel, and can examine Survey the pressure of material in feeder channel.Optionally, pressure sensor 106 may be designed to directly detect the material in nozzle 104 Pressure.It includes linear actuators and needle seal to control switch 108, can control needle seal and be cut between open position and closed position It changes.Linear actuators can be mechanical actuator (it may include lead screw), and hydraulic actuator, (it can be wrapped pneumatic actuator Include pneumatic operated valve) or electromagnetic actuators (it may include solenoid valve).In some embodiments, actuator includes syringe, such as gas Dynamic syringe.In some embodiments, actuator includes spring assistant cylinder.In some embodiments, spring assistant cylinder includes The spring (that is, needle seal is pulled to closed position from open position) of auxiliary seal needle action.In some embodiments, spring Assistant cylinder includes the spring for helping pumpback needle seal (needle seal is pulled to open position from closed position).Work as needle seal When in an open position, the melted material of pressurization can flow through feeder channel and by the extrusion of nozzle 104.It is opened when to control When pass 108 sends out signal, needle seal is reduced to closed position, and the end of needle seal and nozzle 104 by control switch 108 Inner surface engages.

In some embodiments, the material is non-filamentary material, such as powder, granule, gel or paste.Non-linear shape material Material is melted and pressurizes so that it can which the extrusion by nozzle squeezes out.Further described herein is finely controlled particularly viscous The pressure of thick material is to ensure that material can be deposited precisely and accurately.Material can be in feed block using being arranged in confession One or more heaters (such as inside or around barrel, feeder channel and/or print head) in material module are added Heat fusing.In some embodiments, the melting temperature of material is about 50 DEG C or higher, for example, about 60 DEG C or higher, about 70 DEG C or Higher, about 80 DEG C or higher, about 100 DEG C or higher, about 120 DEG C or higher, about 150 DEG C or higher, about 200 DEG C or higher, or About 250 DEG C or higher.In some embodiments, the melting temperature of material is about 400 DEG C or lower, for example, about 350 DEG C or lower, About 300 DEG C or lower, about 260 DEG C or lower, about 200 DEG C or lower, about 150 DEG C or lower, about 100 DEG C or lower, or about 80 DEG C or it is lower.The material squeezed out from nozzle can squeeze out at a temperature of equal to or higher than material melt temp.In some implementations In example, material is in about 50 DEG C or higher, for example, about 60 DEG C or higher, about 70 DEG C or higher, about 80 DEG C or higher, about 100 DEG C or Higher, about 120 DEG C or higher, about 150 DEG C or higher squeeze out under about 200 DEG C or higher, or about 250 DEG C or higher temperature. In some embodiments, material is at about 400 DEG C or lower, for example, about 350 DEG C or lower, about 300 DEG C or lower, about 260 DEG C or more It is low, about 200 DEG C or lower, about 150 DEG C or lower, about 100 DEG C or lower, or squeezed out at about 80 DEG C or lower temperature.

Device of the present invention can be used for accurately and precisely squeezing out cohesive material.In some embodiments, when from setting When standby middle extrusion, viscosity of material has about 100Pas or bigger, for example, about 200Pas or a bigger, about 300Pas or more Greatly, about 400Pas or bigger, about 500Pas or bigger, about 750Pas or bigger, or about 1000Pas or bigger. In some embodiments, viscosity of material have about 2000Pas or lower, for example, about 1000Pas or lower, about 750Pas or It is lower, about 500Pas or lower, about 400Pas or lower, about 300Pas or lower, or about 200Pas or lower.

In some embodiments, which is medicinal materials.In some embodiments, which is inert or biological lazy Property.In some embodiments, which is erodible material or bioerodible material.In some embodiments, should Material is non-soluble materials or abiotic soluble materials.In some embodiments, which is medicinal materials.In some embodiments In, material includes one or more thermoplastic materials, one or more non-thermoplastic materials or one or more thermoplasticity materials The combination of material and one or more non-thermoplastic materials.In some embodiments, which is polymer or copolymer.

In some embodiments, which includes thermoplastic material.In some embodiments, which is thermoplasticity material Material.In some embodiments, which is or the thermoplastic material comprising erodable.In some embodiments, thermoplastic material It is edible (individual being suitble to digest and assimilate).In some embodiments, thermoplastic material is selected from hydrophilic polymer, hydrophobic poly- Conjunction object, swollen polymer, non-swelling polymer, porous polymer, non-porous polymer, eroding polymer (such as resolvability is poly- Close object), pH sensitive polymers, natural polymer, wax-like materials and combinations thereof.In some embodiments, thermoplastic material is fibre The plain ether of dimension, cellulose esters, acrylic resin, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methylol are fine Dimension element, the monoglyceride or diglyceride of C12-C30 aliphatic acid, C12-C30 fatty alcohols, wax, poly- (methyl) acrylic acid, polyethylene Base caprolactam-polyvinyl acetate-polyethyleneglycol-graft copolymer 57/30/13, vinylpyrrolidone-vinyl acetate are total Polymers (PVP-VA), vinylpyrrolidone-vinyl acetate copolymer (PVP-VA) 60/40, polyvinylpyrrolidone (PVP), Polyvinyl acetate (PVAc) and polyvinylpyrrolidone (PVP) 80/20, vinylpyrrolidone/vinyl acetate copolymer (VA64), polyethylene glycol vinyl alcohol graft copolymer 25/75, kollicoat IR- polyvinyl alcohol 60/40, polyvinyl alcohol (PVA or PV-OH), poly- (vinyl acetate) (PVAc), butyl methacrylate-(2- dimethyl aminoethyls) methacrylic acid Ester-methylmethacrylate copolymer 1:2:1, dimethylaminoethyl methacrylate-methacrylate copolymer, acrylic acid Ethyl ester-methyl methacrylate-trimethylammoniumethyl methacrylate chloride copolymer, methyl methacrylate-methyl Methyl acrylate-methacrylic acid copolymer 7:3:1, EUDRAGIT L100 1:2, metering system Acid-ethyl acrylate copolymer 1:1, polyethylene oxide (PEO), polyethylene glycol (PEG), hyperbranched polyester amide, hydroxypropyl first Base cellulose phthalate, hypromellose phthalate, hydroxypropyl methyl cellulose or hydroxypropyl methylcellulose (HMPC), hydroxypropyl methylcellulose acetate succinate or hydroxypropyl methylcellulose succinate (HPMCAS), lactide-second are handed over Ester copolymer (PLGA), carbomer, vinyl-vinyl acetate copolymer, polyethylene (PE) and polycaprolactone (PCL), hydroxypropyl Base cellulose (HPC), polyoxyethylene 40 give birth to hydrogen castor oil, methylcellulose (MC), ethyl cellulose (EC), poloxamer, hydroxyl Propyl methocel phthalic acid ester (HPMCP), poloxamer, rilanit special, oil with hydrogenated soybean, palmitic, stearic Glyceride, Brazil wax, polylactic acid (PLA), polyglycolic acid (PGA), acetylbutyrylcellulose (CAB), polyvinyl acetate are adjacent Phthalic acid ester (PVAP), wax, beeswax, hydrogel, gelatin, hydrogenated vegetable oil, polyvinyl acetal amino lactate (AEA), paraffin, shellac, sodium alginate, cellulose acetate-phthalate (CAP), gum arabic, xanthans, monostearate Glyceride, octadecanoid acid, thermoplastic starch, one kind of derivative (such as its salt, amide or ester) or combination.

In some embodiments, solvable corrosion material includes non-thermoplastic material.In some embodiments, solvable corrosion material is Non-thermoplastic material.In some embodiments, non-thermoplastic material is non-thermoplastic starch, sodium starch glycollate (CMS- Na), sucrose, dextrin, lactose, microcrystalline cellulose (MCC), mannitol, magnesium stearate (MS), powdered silica gel, glycerine, syrup, Lecithin, soybean oil, tea oil, ethyl alcohol, propylene glycol, glycerine, tween, animal tallow, silicone oil, cocoa butter, fatty glyceride are all Intellectual circle, chitosan, cetanol, stearyl alcohol, polymethacrylates, nontoxic polyvinyl chloride, polyethylene, ethane-acetic acid ethyenyl Ester copolymer, silicon rubber or combinations thereof.

Device of the present invention can be used or include using the exemplary materials of method of the present invention, but is unlimited In, poly- (methyl) acrylate copolymer (such as contain one or more aminoalkyl methacrylic acids, methacrylic acid, first Base acrylate and/or ammonium methacrylate Arrcostab, such as with trade (brand) nameThe copolymer that RSPO is sold) and hydroxypropyl Base cellulose (HPC).

In some embodiments, the material includes drug.In some embodiments, the material is mixed with drug.

In material control system, it can be pressurizeed to material using pressure controller.Material is preloaded in barrel, And pressure controller can apply pressure to the material being mounted in advance in barrel.Pressure controller can be motor (such as stepping Motor), valve or any other suitable control device, the controller can drive such as piston, and pressure lead screw or compressed air are (i.e. Pneumatic controller) etc. mechanisms, with into charging basket material apply pressure.Charging basket includes one or more heaters, can be incited somebody to action Material molten.In some embodiments, heater is set in barrel.In some embodiments, heater is arranged in barrel side Face surrounds cylinder.In some embodiments, heater is electric radiation heater, such as electric heating tube or heating coil.Barrel The heater preferably high efficiency heater with high voltage and high-power output.In some embodiments, the heater of barrel has Rated voltage between 110V to 600V.In some embodiments, the heater of barrel has between 210V to 240V Rated voltage.In some embodiments, the heater of barrel is 220V heaters.In some embodiments, the heater of barrel Power between about 30W and about 100W, such as between 40W and 80W, or about 60W.In some embodiments, it heats Device is the electric heating coil outside cylinder.Preferably, barrel is made of heat proof material, such as stainless steel (such as 316L is not Become rusty steel).

Feed block includes the feeder channel for connecting barrel and print head inner nozzle.Material melts or softens in barrel, It flows through feeder channel and flows to nozzle.In some embodiments, one or more heaters are located at feeder channel or feeder channel A part (such as lateral part of feeder channel) it is internal, surrounding or near.One or more heaters, which be used to heat, to be supplied Expect the material in channel.In some embodiments, heater is electric radiation heater, such as electric heating tube or coil.For example, In some embodiments, electric heating tube is placed along the length of feeder channel or at least part length of feeder channel.Heater is excellent Selection of land is with high voltage and powerful high efficiency heater.In some embodiments, feeder channel heater has in 110V Rated voltage between 600V.In some embodiments, feeder channel heater has specified between 210V and 240V Voltage.In some embodiments, feeder channel heater is 220V heaters.In some embodiments, feeder channel heater Power is between about 30W and about 100W, such as between 40W and 80W, or about 60W.In some embodiments, described Device includes one or more temperature sensors, and one or more of temperature sensors are located near the feeder channel or position In in the feeder channel, the temperature sensor is used to measure the temperature of the material in the feeder channel.Feeder channel with The extrusion of nozzle is compared to relatively wide.In some embodiments, feeder channel has between about 1mm and about 15mm, such as Between about 1mm and about 5mm, the diameter between about 5mm and about 10mm or between about 10mm and about 15mm.In exemplary reality It applies in example, feeder channel has the diameter of about 8mm.

The print head of the device includes nozzle, which includes extrusion, and melted material is squeezed out by the extrusion.It squeezes out Mouth is located at distal end of the nozzle relative to feeder channel.When needle seal is in an open position, the material of melting is logical from feeder channel Cross nozzle outflow extrusion.Nozzle includes cone-shaped inner surface, and extrusion is close to the vertex of cone-shaped inner surface.In some embodiments In, the inner surface of nozzle includes liner or bushing.Liner or bushing can be by polytetrafluoroethylene (PTFE) (PTFE) or any other is suitable Material be made.In some embodiments, print head includes one or more heaters, can be located at the nozzle of print head It is interior, surrounding or near.The one or more heater can reach and barrel or confession for the material in heated nozzle, the material Expect the temperature of the material identical in channel or different temperature.In some embodiments, nozzle heater is electric radiation heater, Such as electric heating tube or heating coil.Heater can use voltage more lower than material tube heater or feeder channel heater And/or lower power.In some embodiments, nozzle heater has the rated voltage between 6V to 60V.In some implementations In example, nozzle heater is 12V heaters.In some embodiments, the power of nozzle heater between about 10W and about 60W it Between, such as between 20W and 45W or about 30W.In some embodiments, print head includes being located at nozzle near or within One or more temperature sensors, the temperature for measuring the material in nozzle.

The device includes pressure sensor, which is used to detect print head or the feeder channel close to print head The pressure of interior material.In some embodiments, pressure sensor is connected to computer system, computer system control feed Material is pressurized to specific pressure by module to respond the pressure reported by pressure sensor.For example, computer system can be controlled Pressing pressure controller is applied to the pressure value of the material in barrel to adjust.In some embodiments, the system is anti-as closed loop Feedback system is to maintain the pressure of the approximately constant in device.In some embodiments, reponse system use ratio integral differential (PID) it controls, bang-bang controls, PREDICTIVE CONTROL, fuzzy control, Multimode Control or any other suitable algorithm operate. In some embodiments, Pressure Sensor Precision is in 0.005MPa, in 0.008MPa, in 0.05MPa, and in 0.1MPa, In 0.2MPa, in 0.5MPa or in 1MPa.In some embodiments, the sampling time of pressure sensor is about 20ms or more Or about 2ms or faster soon, such as about 10ms or faster, about 5ms or faster,.In some embodiments, the pressure of material Power is in the about 0.005MPa of required pressure, about 0.008MPa, about 0.05MPa, about 0.1MPa, about 0.2MPa, about 0.5MPa or about It floats in 1MPa.

In some embodiments, which includes one or more temperature sensors.In some embodiments, the device packet Include the temperature sensor in expects pipe or near expects pipe, or the temperature sensor for detecting temperature in expects pipe.In some realities It applies in example, which includes in feeder channel or neighbouring temperature sensor, or for detecting the temperature in feeder channel. In some embodiments, which includes being located at interior print head or neighbouring temperature sensor or for detecting the temperature in nozzle Temperature sensor.In some embodiments, one or more temperature sensors are connected to according to one or more temperature sensing The temperature of device report and control the computer systems of one or more heaters.For example, computer system can control one or Multiple heater for regulating barrels, the temperature of the material in feeder channel and/or nozzle.In some embodiments, which makees It is run for closed loop feedback system, to maintain the temperature of the approximately constant of device or device feature (that is, barrel, nozzle or feeder channel) Degree.The temperature of material in the different components of device can be identical or different.In some embodiments, reponse system use ratio Integral differential (PID) controls, bang-bang controls, predictive controller, Fuzzy control system, Multimode Control or any other conjunction Suitable algorithm controls.

The equipment includes that control switchs.Control switch can be controlled to prevent or allow the material melted from equipment Extrusion outflow.Control switch includes the needle seal that can switch in open position and closed position, wherein being in needle seal Material is prevented to flow through nozzle when closed position.Needle seal extends through at least part of feeder channel and includes tapering point Portion.When needle seal is in the closed position, the cone-shaped inner surface of the tapering point of needle seal and nozzle (such as the extrusion in nozzle Place) engagement.

In some embodiments, any part of the needle seal of contact material does not have protrusion.Protrusion refers to the straight of needle seal Diameter is more than any part of sealing needle shaft or needle seal prolongs the axially outwardly extending any part.Preferably, it avoids closing When sealing needle, the protrusion on needle seal pushes melted material to pass through extrusion.In some embodiments, no matter close entire needle seal is ( Seal needle whether contact material) do not have protrusion.In some embodiments, the part of the not contact material of needle seal includes one or more A protrusion, such as can engage or fracture as depth to prevent needle seal from being driven in feed space with the component of actuator It obtains too far.

The needle seal part of contact material is (that is, be located at feeder channel when needle seal is in an open position or closed position Interior part) it is relatively thin compared with feeder channel, allow the material of melting to be flowed around needle seal, rather than is squeezed out Extrusion.In some embodiments, the maximum gauge with the part of material with about 0.2mm to about 3.0mm of needle seal, For example, about 0.2mm to about 0.5mm, about 0.5mm are to about 1.0mm, and about 1.0mm to about 1.5mm, about 1.5mm is to about 2.0mm, about 2.0mm to about 2.5mm or about 2.5mm to about 3.0mm.In some embodiments, needle seal (including the contact material of needle seal The part of the not contact material of part and needle seal) maximum gauge with about 0.2mm to 3.0mm, for example, about 0.2mm is to about 0.5mm, about 0.5mm are to about 1.0mm, about 1.0mm to about 1.5mm, about 1.5mm to about 2.0mm, about 2.0mm to about 2.5mm or about 2.5mm to about 3.0mm.

In some embodiments, needle seal includes tip at tapering point, as shown in Figure 3A.In some embodiments, sharp The tapering point at end is conical butt, as shown in Figure 3B.Nozzle and needle seal include conical surface so that the cone of needle seal Cone-shaped inner surface of the shape end towards nozzle.Here " cone angle " refers to the angle on the vertex of engagement surface.In conical butt In the case of tip, " cone angle " refers to the vertex of extrapolation engagement surface.The cone angle of the tapering point of needle seal is in Fig. 3 A and Fig. 3 B With indicating.As shown in Figure 3 C, the cone angle of nozzle is indicated by β.In some embodiments, the cone angle of the tapered end of needle seal is about 60 ° or smaller, such as about 50 ° or smaller, 45 ° or smaller, 40 ° or smaller, 35 ° or smaller, 30 ° or smaller, 25 ° or smaller, 20 ° or or smaller or 15 ° or smaller.In some embodiments, the cone angle (α) of needle seal is equal to or less than inner nozzle surface Cone angle (β).In some embodiments, the ratio between the cone angle (α) of the cone angle of inner nozzle surface (β) and needle seal is about 1：1 to about 4： 1, or about 1：1 to about 3：1, or about 1：1 to about 2：1.

By reducing needle seal towards extrusion, needle seal is located in closed position, and needle seal is aligned with extrusion at this time. When needle seal is in an open position, it is pressurized and the material melted can flows through extrusion, but when needle seal is in close stance When setting, it is prevented from flowing, it is engaged with the inner surface of nozzle in the position.When the cone angle (β) of inner nozzle surface is more than sealing When cone angle (α) of needle, the tapering point of needle seal is engaged with the inner surface of nozzle at extrusion.In some embodiments, extrusion With about 0.1mm or bigger, for example, about 0.15mm or bigger, about 0.25mm or bigger, about 0.5mm or bigger, 0.75mm or more Big diameter.In some embodiments, extrusion has about 1mm or a smaller, such as about 0.75mm or smaller, about 0.5mm or more It is small, about 0.25mm or smaller, about 0.15mm or less diameter.Preferably thin needle seal tapering point base portion, with limitation when close Envelope needle drives towards the material melted when closed position and is squeezed through extrusion.In some embodiments, needle seal tapered end Maximum gauge (that is, bottom of taper) and the ratio of the diameter of extrusion are about 1:0.8 to about 1:0.1, such as about 1：0.8 to about 1：0.7, about 1：0.7 to about 1：0.6, about 1：0.6 to about 1：0.5, about 1：0.5 to about 1：0.4, about 1：0.4 to about 1：0.3, about 1：0.3 to about 1：0.2, or about 1：0.2 to about 1：0.1.

Needle seal preferably includes material firm and flexible.Exemplary materials include but not limited to stainless steel, polytetrafluoro Ethylene (PTFE) and carbon fiber.In some embodiments, the inner surface of nozzle includes flexible liner or bushing, can sealed Needle damage of the limitation to needle or nozzle when open position or closed position switch repeatedly.In some embodiments, it pads or serves as a contrast Set is made of polytetrafluoroethylene (PTFE) (PTFE).

The needle seal of control switch is controlled using actuator, which can be located in open position by needle seal (that is, making the inner surface of the tapering point no longer engagement nozzle of needle seal by lift-off seal needle) or closed position are (that is, pass through drop Low needle seal makes the tapered end of needle seal be engaged with the inner surface of nozzle).In some embodiments, actuator is pneumatically to cause Dynamic device, can be controlled using the air pressure in actuator.In some embodiments, actuator is mechanical actuator, can be led to It crosses and needle seal is raised and lowered using one or more gears and motor.In some embodiments, actuator includes solenoid valve Or electrostrictive polymers.

Fig. 2A shows the cross-sectional view of the exemplary means according to the present invention by increasing material manufacturing come deposition materials.Material Material can be loaded onto in the barrel 202 of feed block, and piston 204 applies pressure by being pushed into barrel 202 to material Power.Piston 204 is connected to pressure controller by leading arm 206.Piston 204 is reduced to increase by the motor of such as stepper motor The pressure of material or lifting up piston are to reduce the pressure of material in casing drum 202.It can use in barrel or around barrel Heater by the material in barrel 202 be heated to or higher than material melting temperature.Melted material from barrel 202 flows through confession Expect that channel 208, the feeder channel 208 are connected to the print head 210 including nozzle 212.Pressure sensor 214 is located at feeder channel 208 end, and close to print head 210, and be used to detect the pressure of the material close to print head.In some embodiments In, pressure sensor 214 is oriented the pressure of material in detection print head 210.The pressure that pressure sensor 214 can will detect Power is transferred to computer system, and the operable pressure controller of the computer system (or motor of pressure controller) is to reposition Piston 204 and the pressure for controlling the material in barrel 202.This can be operated in reponse system, and wherein the variation of pressure is by pressing Force snesor 214 detects, and computer system further operating pressure controller.

The device includes control switch 216 comprising needle seal 218 and linear actuators 220.Needle seal 218 includes connecing Close the lower end 224 of the upper end 222 and taper of actuator 220.Needle seal 218 extends to print head 210 across feeder channel 208 In.Actuator 220 controls needle seal 218 between open position (raising) and closed position (reduction).When needle seal 218 is set to When closed position, the cone-shaped inner surface of 224 engagement nozzle 212 of tapered end of needle seal 218 is to prevent melted material from flowing through Nozzle.In order to open nozzle 212 and melted material be allowed to flow through extrusion, actuator 220 controls needle seal 218 and is promoted with passing through Needle seal 218 is located in open position by needle seal 218, to make tapered lower end 224 and the inner surface of nozzle 212 detach.Figure The enlarged view of print head 210 in the case that 2B shows and engagement nozzle 212 in the closed position in needle seal 218. When closed position, the tapering point 224 of needle seal 218 is closed by being connected with the cone-shaped inner surface 212 of nozzle to be inserted into extrusion 226.Therefore the melted material in feeder channel 208 is prevented to flow through extrusion 226.It is detected and is printed by pressure sensor 214 The pressure of material in first 210 or near it, and can be with operating pressure controller to prevent from being in close stance when needle seal 218 Excessive pressure is accumulated when setting in a device.

Needle seal 218 extends through feeder channel 208 and enters print head 210.When needle seal 218 switches from open position When to closed position, the well-designed melted material prevented in feeder channel 208 is pushed out extrusion 226.The cone of needle seal 218 Shape end 224 allows needle seal 218 to pierce through the material melted, to allow the material of melting to flow up and surround closed sealing Needle 218, rather than be pushed downwards.

Pneumatic actuator 220 includes solenoid valve, which flows into air chamber 226 for controlling gas, which can To drive the center-pole 228 for the upper end 222 for being attached to needle seal 218 upward or downward.High pressure gas is flowed into from 230 lower section of partition board Gas chamber 226 removes gas above partition board 230, to make partition board 230 move up, is located in needle seal 218 beats in this way Open position.Gas is removed from 230 lower section of partition board or applying high pressure gas above partition board 230 can be such that partition board 230 moves down, Needle seal 218 is located in closed position by this.

Fig. 4, which is shown, is connected to needle seal with the exploded view of the parts for the pneumatic actuator for controlling needle seal.Partition board 402 In the gas chamber of pneumatic actuator, and center-pole 404 is for example connected to by screw-thread fit.Center-pole 404 for example passes through Screw-thread fit is connected to adapter 406.Adapter 406 is for example attached to needle seal by screw-thread fit or by compression fit 408.For example, the lower part of adapter 406 may include opening, and the top of needle seal 408 can be by filling in needle seal 408 Enter the opening of adapter 406 and is closely fitted into opening.Needle seal 408 is by washer 410, and the washer 410 is by fixed spiral shell Mother 412 positions.Fixing nut 412 is fixed on washer in transfer block, to be connected with equipment other parts.Such as Fig. 2A institutes Show, transfer block 232 is located in 208 top of feeder channel, is aligned with the nozzle 212 of print head 210.Transfer block channel 234 passes through Transfer block 232 enters feeder channel.Washer 236 is embedded in the opening at 232 top of transfer block, and the aperture efficiency channel 234 is wide, to Prevent washer 236 from being moved towards print head 210.Washer 236 can be made of inertia pliable material, such as plastics or synthetic rubber, And feeder channel 208 is sealed to prevent melted material from leaking.In some embodiments, washer uses polytetrafluoroethylene (PTFE) (PTFE).Fixing nut 238 is fixed, such as by screw-thread fit, arrives transfer block 232, and the position of retaining washer 236.Therefore, Washer 236 is in a fixed position relative to print head 210 and nozzle 212.Needle seal 218 passes through fixing nut 238 and washer 236 In hole to reach feeder channel 208.The permission needle that is sized in the hole passes through, and can be controlled and be moved by actuator 216 It is dynamic, but the material leakage of melting cannot be caused very much greatly.

Feed block includes one or more heaters for melted material.Heater can be placed on comprising material Around or within charging basket, feeder channel and/or print head.Fig. 5 A show the longitdinal cross-section diagram of a part for the device, figure 5B shows that the cross-sectional view at plane " A-A ", Fig. 5 C show the non-cross-sectional of the device.In some embodiments, the dress The heater 502 for including the barrel 504 around the device is set, which can heat and melting is contained in barrel 504 Material.Heater 502 can be the winding heater for example around the outside of barrel 504.In some embodiments, heater It is arranged in barrel.The material being placed in barrel is initially melted by heater in barrel, and pressure passes through piston 506 It is applied to material.Then, melted material flows to feeder channel 508 from barrel 504.In some embodiments, in order to ensure material It is kept at a certain temperature in feeder channel 508, one or more heaters can be placed in feeder channel 508 nearby or positioned at confession Expect in channel 508.Fig. 5 B and Fig. 5 C show that two heaters 510a and 510b, each heater are located at feeder channel 508 Both sides, and it is adjacent with feeder channel 508.In some embodiments, heater 510a and/or 510b covers feeder channel 508 Length or the side for covering feeder channel 508.In some embodiments, adjacent with feeder channel 508 or in feeder channel 508 One or more heaters be heating rod.In some embodiments, adjacent with feeder channel 508 or in feeder channel 508 One or more heaters be coil around feeder channel 508.Heat one or more heaters in feeder channel 508 Ensure that material keeps melting, and has appropriate viscosity to realize expected flowing at a given pressure.In some embodiments, The print head 512 of device includes one or more heaters 514, ensures that material keeps melting and have in nozzle 516 Suitable viscosity.

In some embodiments, which includes one or more temperature sensors, can be located in equipment one Or at multiple positions and can be with the temperature of the material in detection device, such as in barrel, in feeder channel or in print head. In embodiment in Fig. 5 A- Fig. 5 C, include first temperature sensor 518 adjacent with feeder channel 508 and with 512 phase of print head Adjacent second temperature sensor 520.The temperature sensor 518 of neighbouring feeder channel 508 is in feeder channel 508 1 in figure Side, but temperature sensor 518 is alternatively located in any position of the length direction along feeder channel 508.518 He of temperature sensor One or more heaters (for example, 510a and 510b) can be used as melting the closed loop feedback system of the material in feeder channel 508, The closed loop feedback system may insure that the material in feeder channel keeps the temperature of approximately constant.For example, temperature sensor 518 can The temperature of measurement is transferred to computer system, and computer system can operate one or more heater 510a and 510b is to ensure the temperature of approximately constant.Temperature sensor 520 in the print head 512 of device can be with one in print head Or multiple heaters 514 work together in closed loop feedback system, to ensure the temperature of the approximately constant of the material in print head. Reponse system can be with use ratio-Integrated Derivative (PID) controller, bang-bang controllers, predictive controller, fuzzy control System, expert system control device or any other suitable control algolithm.In some embodiments, one or more of device Material in system is heated to the melting temperature equal to or higher than material by heater.In some embodiments, one or more Heater heats the material to about 60 DEG C or higher temperature, for example, about 70 DEG C or higher, 80 DEG C or higher, 100 DEG C or higher, 120 DEG C or higher, 150 DEG C or higher, 200 DEG C or higher or 250 DEG C or higher.In some embodiments, one or more to add Hot device heats the material to about 300 DEG C or lower, for example, about 260 DEG C or lower, 200 DEG C or lower, 150 DEG C or lower, 100 DEG C Or lower or 80 DEG C or lower temperature.In some embodiments, one or more heaters will at the different location of device Material is heated to different temperature.For example, in some embodiments, material is heated to the first temperature in barrel, feed is logical The third temperature in second temperature and print head in road, each temperature can be identical temperature or different temperature.It lifts For example, a kind of material can be heated to 140 DEG C in charging basket and feeder channel, but 160 DEG C can be heated in print head. High-precision temperature control may be implemented in feedback control system.In some embodiments, temperature control is at 0.1 DEG C of target temperature It is interior, in 0.2 DEG C of target temperature, in 0.5 DEG C of target temperature or in 1 DEG C of target temperature.

The device includes one or more pressure sensors, can be with the pressure of material in detection device.In some implementations In example, pressure sensor is used to detect the pressure of the material in print head or in the feeder channel of neighbouring print head.In some realities It applies in example, pressure sensor is placed in print head or the neighbouring position for feeding channel and close print head.Pressure sensor It can work together with the pressure controller in closed loop feedback system, the pressure of approximately constant is provided with the material into device. For example, when pressure sensor detects that pressure declines, reponse system can send out signal to increase material to pressure controller Pressure (for example, by reduce piston, increase barrel in air pressure, rotation pressure lead screw etc.).Similarly, when pressure passes When sensor detects pressure increase, reponse system can send out signal to reduce the pressure of material (for example, logical to pressure controller Lifting up piston is crossed, the air pressure in barrel body, rotation pressure lead screw etc. are reduced).Constant pressure ensures the melting material in device Expect the extrusion that nozzle is passed through with constant rate of speed when needle seal is in an open position.However, when needle seal is in the closed position When, constant pressure increases and (for example, by lifting up piston, reduces the air pressure in barrel, rotation pressure lead screw etc.) may The material of melting is caused to pass through nozzle leakage.In addition, the reponse system including pressure sensor and pressure controller is in needle seal When being switched to closed position again from open position or being switched to open position again from closed position, keep in systems approximate Constant pressure.When needle seal is switched to open position from closed position, this makes " oblique ascension " of rate of extrusion to minimize, because Need not in raising system material pressure.Reponse system can be with use ratio-Integrated Derivative (PID) controller, bang- Bang controllers, predictive controller, Fuzzy control system, expert system control device or any other suitable control algolithm. In some embodiments, the sampling rate of pressure sensor is about 20ms or faster, such as about 10ms or faster, about 5ms Or faster, or about 2ms or faster.In some embodiments, pressure is controlled in the 0.05MPa of goal pressure, target In the 0.1MPa of pressure, in the 0.2MPa of goal pressure, in the 0.5MPa of goal pressure or in the 1MPa of goal pressure.

Fig. 6 shows another example of equipment of the present invention.Material is loaded onto the barrel 602 of feed block In, and pressure lead screw 604 (that is, screw-plunger) can apply pressure to the material in barrel 602.In order to increase to material Pressure, pressure controller 606 (for example, stepper motor) rotate first gear 608, and first gear 608 is pivotally attached to pressure silk The second gear 610 of bar 604.Material in barrel 602 can be heated by the heater 614 around barrel.From barrel 602 Interior melted material flow to the print head 618 including nozzle 620 by feeder channel 616.The equipment may include that pressure passes Sensor 630, the pressure sensor 630 be used to detect the pressure of barrel 602, channel 616 and/or the material in print head 618. Pressure sensor 630 can be with operating pressure controller by the pressure transmission detected to computer system, computer system 608 to reposition pressure lead screw 604 and control the pressure of the material in barrel 602.This control can be in reponse system Operation, the wherein variation of pressure is detected by pressure sensor 630, and computer system further operating pressure controller.Fig. 6 Shown in device include control switch comprising along axis identical with barrel 602 needle seal 622 and actuator 624.Sealing Needle 622 includes upper end and the inferior pyramidal end (not shown) for being connected to actuator 624.Actuator 624 in open position (raising) and Needle seal 622 is controlled between closed position (reduction).When needle seal 622 is placed in closed position, the tapering point of needle seal 622 The cone-shaped inner surface of portion's engagement nozzle 622 is to prevent melted material from flowing through nozzle.Print head 618 can also include one or more Heater 626 and temperature sensor 628, can operate in reponse system.

In certain embodiments, the increasing material manufacturing system comprising multiple (for example, two as described in the present invention Or more, three or more, four or more, five or more or six or more) device comprising feed block is matched There is control switch (including needle seal and nozzle with the tapered end that can switch in open position and closed position).It is each only Material in vertical device can be identical or different.For example, in some embodiments, system includes two devices and two different Material (that is, the first material and second material).In some embodiments, which includes three devices and three kinds of different materials (that is, the first material, the second material and third material).In some embodiments, system includes four devices and four kinds of different materials Expect (that is, the first material, the second material, third material and the 4th material).In some embodiments, system include five devices and Five kinds of different materials (that is, the first material, the second material, third material, the 4th material and the 5th material).In some embodiments In, system include six devices and six kinds of different materials (that is, the first material, the second material, third material, the 4th material, the 5th Material and the 6th material).In some embodiments, increasing material manufacturing system includes being mounted with the first device and loading of the first material There is the second device of the second material, wherein the first material and the second material are different.Different feed blocks in increasing material manufacturing system Extrudable different materials are to form multicomponent printed product, such as multicomponent pharmaceutical dosage form (such as tablet).It is supplied when one of When material module is in active state when (that is, needle seal is in an open position), other feed blocks in device do not work (that is, needle seal is in the closed position).By coordinating needle seal in open position or the position of closed position, which can be It is switched fast between activity feeding system.Fig. 7 shows a part for the exemplary system including three feed blocks, each to be System has different print heads 702,704 and 706.Stamp pad 708 can move on x, y and z-axis, and product is in correct print head Under, it can be with extruded material to generate product 710 (such as tablet).

In some embodiments, equipment (or system including multiple equipment) described herein is connected to computer system, The computer system can be with any one or more of the various assemblies of control device.For example, in some embodiments, calculating The one or more heaters of machine system control, pressure controller and/or control switch.In some embodiments, computer system One or more heating are controlled in response to the temperature (that is, in feedback control) detected by one or more temperature sensors Device.In some embodiments, computer system operates pressure in response to the pressure detected by one or more pressure sensors Force controller.The computer system includes one or more processors and computer-readable memory, may include for grasping Make the instruction of the equipment.In some embodiments, computer system is desktop computer, and laptop, mobile device is (such as Mobile phone or tablet computer), programmable logic controller (PLC) (PLC) or microcontroller.Computer system may include for example locating Manage device, memory, memory and input-output apparatus (for example, monitor, keyboard, disc driver, internet connection etc.).So And computing system can also include for execute method described herein some or all aspect and/or for operate here The equipment of description and the circuit of system or other specialized hardwares.In some operation settings, computing system can be configured as packet The system for including one or more units, each unit are configured as with software, and hardware or some combinations come the one of implementation procedure A little aspects.The main system of exemplary computer system may include the mainboard for having the part input/output (" I/O "), one or Multiple central processing unit (" CPU ") and memory portion, the memory portion can have associated flash card.I/O Part may be coupled to display, keyboard, disk storage unit, medium driving unit and/or equipment described herein or system In one.Media-driven unit can be able to include program (that is, instruction) with read/write and/or data is computer-readable Medium.At least some values of result based on the above process can be saved for then using.Further, it is possible to use nonvolatile Property computer-readable medium store (for example, having body) one or more computer programs, these programs hold by computer The row above method.Computer program can use general programming language (for example, Pascal, C, C++, Java, Python, JSON etc.) Or certain specific language is write.

In some embodiments, computer system include one or more processors and including for by increasing material manufacturing come The computer-readable memory of the instruction of printed product (such as pharmaceutical dosage form, such as tablet).In some embodiments, computer System carrys out operation-control switch in response to the instruction of printed product.In some embodiments, include for the instruction of printed product Use the instruction of successively extrusion method printed product.

The instruction of product for printing such as pharmaceutical dosage form can be come using any one or more of distinct methods It generates, these methods include direct coding, from the export of entity CAD model or the computer interface of other specific three-dimensional printers And application software.These instructions may include the information in relation to amount of droplets and spatial position and general print parameters, such as Each drop spacing of linear dimension (X, Y, Z) and the volume or quality of each drop.It, can be with for one group of given material These parameters are adjusted to improve the quality of created structure.The whole resolution of generated structure is powder particle size, stream The function of body drop size, print parameters and material property.

The step of may include melting and pressurised material by increasing material manufacturing deposition materials or the method for manufacturing product；Make material Flow through the extrusion of the nozzle including cone-shaped inner surface；Monitor the pressure of the material in nozzle or close to nozzle；Make needle seal Tapering point is engaged with the cone-shaped inner surface of nozzle, to close extrusion and prevent the flowing of melted material；And pumpback needle seal Tapered end, the flowing for passing through extrusion to restorer.In some embodiments, this method uses as described herein Equipment execute.In some embodiments, which includes multiple feed blocks, wherein each feed block is configured with control Switch.This method may include from the first feed block print the first material and from the second feed block print the second material, wherein When the second material is printed from the second feed block, the needle seal of the first feed block is in the closed position, and when the first material When material is printed from the first feed block, the needle seal of the second supply system is in the closed position.In some embodiments, this method It is executed with cooked mode in batches.In some embodiments, the device or system are controlled to pattern work in batches.Term " pattern in batches " refers to the operating mode of the wherein product (such as pharmaceutical dosage form) of manufacture predetermined quantity.In some embodiments In, this method is executed with continuous operation mode.In some embodiments, device or system work in a continuous mode.Term is " continuous Pattern " refers to that operating mode, wherein equipment or system have worked predetermined time period or the list until being used for predetermined amount Kind or multiple material.

In some embodiments, the method for manufacturing product by increasing material manufacturing includes first material that melts and pressurize；Make First material flows through the first extrusion of the first jet including cone-shaped inner surface；Make the tapered end of the first needle seal with The cone-shaped inner surface of first jet engages, to close the first extrusion and prevent the flowing of the first material of melting；Melting is simultaneously Pressurize second of material；And extract the tapered end of the second needle seal out from the cone-shaped inner surface of second nozzle, to start to make Second material flows through the second extrusion.In some embodiments, this method includes, for example, being received from computer system for making Make the instruction of product.

In some embodiments, included the following steps by the method that increasing material manufacturing produces pharmaceutical dosage form (such as tablet)： Melting and pressurization medicinal materials；Monitor the pressure of the material in nozzle or close to nozzle；Material is set to flow through including cone-shaped inner surface Nozzle extrusion；The tapering point for making needle seal is engaged with the cone-shaped inner surface of nozzle, to close extrusion and prevent molten Melt the flowing of material；And the tapered end of pumpback needle seal, the flowing for passing through extrusion to restorer.In some embodiments In, medicinal materials include drug.In some embodiments, this method is executed using equipment as described in the present invention.At some In embodiment, which includes multiple feed blocks, wherein each feed block is switched configured with control.This method may include from First feed block prints the first material and prints the second material from the second feed block, wherein when the second material is fed from second When module prints, the needle seal of the first feed block is in the closed position, and when the first material is printed from the first feed block When, the needle seal of the second feeding system is in the closed position.In some embodiments, this method further includes in monitoring first jet Or the pressure of the first material near first jet；Or the pressure of the second material near monitoring second nozzle or second nozzle.

In some embodiments, include the first medicinal material that melts and pressurize by the method that increasing material manufacturing produces pharmaceutical dosage form Material；The first medicinal materials are made to flow through the first extrusion of the first jet including cone-shaped inner surface；Make the taper of the first needle seal End is engaged with the cone-shaped inner surface of first jet, to seal the first extrusion and prevent the flowing of the first material of melting； Second medicinal materials are melted and pressurizeed；And extract the tapered end of the second needle seal out from the cone-shaped inner surface of second nozzle, Thus the second medicinal materials is made to flow through the second extrusion.In some embodiments, the first medicinal materials or the second medicinal materials are Erodible material.In some embodiments, the first medicinal materials or the second medicinal materials include drug.In some embodiments, This method further includes the instruction for example received from computer system for manufacturing pharmaceutical dosage form.In some embodiments, this method Further include the pressure for monitoring the first material in first jet or near first jet；Monitoring second nozzle or second nozzle it is attached The pressure of nearly second material.

In some embodiments, method according to the present invention or the pharmaceutical dosage form manufactured using described device or system Including multilayered structure, the multilayered structure includes multilayer the first corrosion material mixed with drug, wherein described mix with drug The first corrosion material it is related to the rate of release of drug.Pharmaceutical dosage form such as oral Pharmaceutical dosage forms can be based on control various parameters and carry For any drug target release profiles, such as the thickness of the first corrosion material layer that is mixed with drug, the first corrosion material layer The drug quality score of surface area and the first corrosion material layer.Drug target release profiles with drug or a variety of drugs Pharmaceutical dosage form easily can be designed and be printed using increasing material manufacturing device of the present invention.

Method according to the present invention is designed to expire using the pharmaceutical dosage form of device manufacturing of the present invention Foot-eye drug release patterns.In some embodiments, pharmaceutical dosage form is custom design (such as personalised drug) with full Foot-eye drug release patterns.In some embodiments, pharmaceutical dosage form includes one or more layers, including mixed with drug first Corrosion material, wherein in second of material that the first corrosion material insertion is not mixed with drug.It is released with desired drug The pharmaceutical dosage form for putting curve can be with for example, design in the following manner：(a) selection is used to form the first corrosion of pharmaceutical dosage form Material and the second material；(b) erosion rate of the first corrosion material is obtained；(c) rate of release based on drug and desired Drug release patterns determine the thickness in every layer, surface area and/or drug quality score.In some embodiments, pharmaceutical dosage form It also include the extra play of one layer or multiple solvable corrosion materials of the third mixed with the second drug.

In some embodiments, pharmaceutical dosage form includes two or more drugs, for example, about 5 kinds or more, 10 kinds or more More, any one of 20 kinds or more, 30 kinds or more or 50 kinds or more, wherein each drug has desired drug Release profiles.In some embodiments, oral Pharmaceutical dosage forms include two or more drugs, and wherein at least two kinds of drugs have Different expectation drug release patterns.

The expectation release profiles of drug can be adjusted according to the material and design used in production pharmaceutical dosage form.One In a little embodiments, two or more different materials of the production and application of pharmaceutical dosage form, can use device of the present invention with One or more layers deposition, the layer can be identical or different.In some embodiments, the pharmaceutical dosage form includes and is mixed with drug The first material first layer and the second material not mixed with drug the second layer.In some embodiments, the drug agent Type includes multilayered structure, and the multilayered structure includes one or more layers first corrosion material for being mixed with drug, wherein described the In the second material that the insertion of one corrosion material is not mixed with drug.The corrosion of the first corrosion material mixed with drug can be with drug The rate of release of drug is related in dosage form.

In some embodiments, it is desirable to drug release patterns be included in administration or drug is then begun to from oral medicine agent Time point after type (for example, being used for enteric coating oral Pharmaceutical dosage forms) release, what drug was discharged from oral Pharmaceutical dosage forms Always (accumulate) score or percentage.In some embodiments, drug target release profiles are predetermined.

In some embodiments, once the first corrosion material layer comprising drug is exposed to such as oral fluid or stomach and intestine (GI) in the solution of liquid, drug will start to discharge from oral Pharmaceutical dosage forms.In some embodiments, the target of oral Pharmaceutical dosage forms Drug release patterns are the periods discharged completely to contained drug in oral Pharmaceutical dosage forms from oral medication.In some embodiments In, desired drug release patterns are included in the initial delay phase before desired drug release period, and the wherein initial delay phase is Patient's specific period or the period of estimation, such as the peroral dosage form due to the use of enteric coatings.

In some embodiments, the required drug release patterns of oral Pharmaceutical dosage forms include zero order delivery profile, and level-one is released Put curve, sustained release curve, pulsed release profile, iterative pulse release profiles, immediate release profile, elution profiles or combinations thereof.

In some embodiments, the total time of the drug target release profiles of oral Pharmaceutical dosage forms is about 1 hour to about 72 Hour, it is such as about 1 hour to about 6 hours, about 1 hour to about 12 hours, about 1 hour to about 18 hours, about 1 hour to about 24 small When, about 1 hour to about 30 hours, about 1 hour to about 36 hours, about 1 hour to about 42 hours, about 1 hour to about 48 hours, about 1 hour to about 54 hours, about 1 hour to about 60 hours or in about 1 hour to about 66 hours it is any.In some embodiments, The total time of the drug target release profiles of oral Pharmaceutical dosage forms is about 1 hour, and 2 hours, 3 hours, 6 hours, 8 hours, 10 is small When, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 26 hours, 28 hours, 30 hours, 32 is small When, 34 hours, 36 hours, 40 hours, 42 hours, 44 hours, 46 hours, 48 hours, 50 hours, 52 hours, 54 hours, 56 is small When, it is any in 58 hours, 60 hours, 62 hours, 64 hours, 66 hours, 68 hours, 70 hours or 72 hours.In some realities Apply in example, the expectation drug release patterns of oral Pharmaceutical dosage forms be more than total time or about 6 hours, be more than or about 12 hours, greatly In or about 18 hours, be more than or about 24 hours, be more than or about 30 hours, be more than or about 36 hours, be more than or about 42 hours, be more than Or about 48 hours, it is more than or about 54 hours, is more than or about 60 hours, is more than or about 66 hours or is more than or about 72 hours.One In a little embodiments, the expectation drug release patterns of oral Pharmaceutical dosage forms be less than total time or about 6 hours, be less than or about 12 is small When, it is less than or about 18 hours, is less than or about 24 hours, be less than or about 30 hours, be less than or about 36 hours, is less than or about 42 is small When, it is less than or about 48 hours, is less than or about 54 hours, be less than or about 60 hours, is less than or about 66 hours or is less than or about 72 is small When.

In some embodiments, one or more corrosion materials are suitable for mixing with drug.In some embodiments, with medicine The corrosion material of object mixing does not have chemical reactivity with the drug.In some embodiments, corrosion material is to be based on and medicine The adaptability of object mixing carrys out selection.In some embodiments, corrosion material is to be based on not having chemical reaction with the drug Activity carrys out selection.

In some embodiments, the material mixed with drug is substantially to be dissoluted within the personal oral Pharmaceutical dosage forms phase The material of (for example, substantially completely corrosion or substantially completely dissolving).In some embodiments, mixed with drug in oral Pharmaceutical dosage forms The corrosion material of conjunction oral Pharmaceutical dosage forms in time in individual almost all be dissoluted.In some embodiments, it takes orally The the first corrosion material mixed with drug in pharmaceutical dosage form is almost complete within the period expected in the individual in oral Pharmaceutical dosage forms Portion is dissoluted.In some embodiments, the first corrosion material mixed with drug in oral Pharmaceutical dosage forms is less than about 72 hours Interior, for example, less than about 48 hours, 36 hours, 24 hours, 18 hours, 12 hours, 10 hours, 8 hours, 6 hours, 4 hours, 2 is small When or 1 hour in any time almost all be dissoluted.

In some embodiments, the erosion rate of the first corrosion material mixed with drug is in about 0.1 mm hr to about Between 4 mm hrs.In some embodiments, the erosion rate of the first corrosion material mixed with drug is greater than about 0.1 milli M/h, it is greater than about 0.2 mm hr, 0.4 mm hr, 0.6 mm hr, 0.8 mm hr, 1.0 millis M/h, 1.5 mm hrs, 2.0 mm hrs, 2.5 mm hrs, 3.0 mm hrs, 3.5 mm hrs or 4.0 It is any in mm hr.In some embodiments, the erosion rate of the first corrosion material mixed with drug is less than about 0.1 Mm hr, for example, less than about 0.2 mm hr, 0.4 mm hr, 0.6 mm hr, 0.8 mm hr, 1.0 millis M/h, 1.5 mm hrs, 2.0 mm hrs, 2.5 mm hrs, 3.0 mm hrs, 3.5 mm hrs or 4.0 It is any in mm hr.

The thickness of deposition materials (material mixed with drug or the material not mixed with drug) can significantly change institute The release profiles of the pharmaceutical dosage form of manufacture.Device and system described herein allow to enhance the control to product thickness, because of dress The pressure set is finely controlled at and controls the leakage of switch limitation extruded material.In addition, device limitation of the present invention " slow to rise " of the rate of extrusion of extruded material, this helps preferably to control material thickness.

In some embodiments, the pharmaceutical dosage form (such as tablet) of desired drug release patterns is provided by increasing material manufacturing Method include the following steps：First material of melting and compression package drug containing；Make material flow through including cone-shaped inner surface First extrusion of one nozzle；The tapering point of first needle seal is engaged with the cone-shaped inner surface of first jet, to closing the One extrusion and the flowing for preventing the first melted material；It melts and second material that pressurizes；It is returned from the cone-shaped inner surface of second nozzle The tapered end for taking out the second needle seal, to make the second material flow through the second extrusion.In some embodiments, this method includes Monitor the pressure of the first material in first jet or near first jet.In some embodiments, this method includes monitoring the The pressure of the second material in two nozzles or near second nozzle.In some embodiments, this method uses as described herein Device or system execute.

Specific embodiment

Embodiment 1. it is a kind of by increasing material manufacturing come the device of deposition materials, including：

Feeding system, the feeding system is used to melt and the material that pressurizes, the feeding system include feeder channel, the confession Material channel is connected to the print head including nozzle, and the nozzle includes cone-shaped inner surface and the extrusion for printed material；

Pressure sensor, the pressure sensor are used to detect in the feeder channel near the nozzle or the nozzle The pressure of material；With

Control switch comprising the needle seal that can switch in open position and closed position, the needle seal extends through described A part for feeder channel and include tapering point；

The tapered end of the wherein described needle seal engages the cone-shaped inner surface of the nozzle, at the needle seal Material is prevented to flow through the nozzle when closed position.

Embodiment 2. is according to the device of embodiment 1, wherein the material is non-wire rod.

Device of the embodiment 3. according to embodiment 1 or 2, any part of the wherein needle seal of contact material all do not have Protrusion.

Device of the embodiment 4. according to any one of embodiment 1-3, wherein pressure sensor are connected to department of computer science Material is pressurized to desired by system, the computer system operation feeding system with responding the pressure reported by pressure sensor Pressure.

Device of the embodiment 5. according to any one of embodiment 1-4, wherein the pressure of the material is in desired pressure About 0.05MPa in.

Device of the embodiment 6. according to any one of embodiment 1-5, wherein the feeding system includes piston and company It is connected to the barrel of the feeder channel, and the wherein described piston is operated to control the pressure of material in the barrel.

Device of the embodiment 7. according to embodiment 6, wherein the piston is driven using stepper motor.

Device of the embodiment 8. according to any one of embodiment 1-7, wherein the tapered end of the needle seal Including tip.

The tapering point of device of the embodiment 9. according to any one of embodiment 1-7, wherein needle seal is frustum of a cone Body.

Device of the embodiment 10. according to any one of embodiment 1-8, wherein the cone-shaped inner surface of the nozzle has The tapering point of first cone angle and the needle seal has the second cone angle；And wherein described second cone angle and described first Cone angle is identical or less than first cone angle.

Device of the embodiment 11. according to embodiment 10, wherein second cone angle is about 60 ° or smaller.

Device of the embodiment 12. according to embodiment 10 or 11, wherein second cone angle is about 45 ° or smaller.

Device of the embodiment 13. according to any one of embodiment 10-12, wherein first cone angle and described second The ratio of cone angle is about 1：1 to about 4：1.

Device of the embodiment 14. according to any one of embodiment 1-13, wherein the extrusion has about 0.1mm extremely The diameter of about 1mm.

Device of the embodiment 15. according to any one of embodiment 1-14, wherein the tapered end has about 0.2mm To the maximum gauge of about 3.0mm.

Device of the embodiment 16. according to any one of embodiment 1-15, wherein extrusion have diameter, and taper End has maximum gauge, and the maximum gauge of tapering point and the ratio of extrusion diameter are about 1:0.8 to about 1:0.1.

The device of any one of 17. embodiment 1-16 of embodiment, wherein when being squeezed out from device, material has about 100Pas or higher viscosity.

The device of any one of 18. embodiment 1-17 of embodiment, wherein when being squeezed out from device, material has about 400Pas or higher viscosity.

The device of any one of 19. embodiment 1-18 of embodiment, wherein the material is melted at about 50 DEG C to about 400 DEG C.

The device of any one of 20. embodiment 1-19 of embodiment, wherein material at a temperature of about 50 DEG C to about 400 DEG C from Nozzle squeezes out.

The device of any one of 21. embodiment 1-19 of embodiment, wherein material at a temperature of about 90 DEG C to about 300 DEG C from Nozzle squeezes out.

Device of the embodiment 22. according to any one of embodiment 1-21, wherein control switch includes will be described Needle seal is located in the actuator of the open position or the closed position.

Device of the embodiment 23. according to embodiment 22, wherein actuator are pneumatic actuators.

Device of the embodiment 24. according to embodiment 22, wherein actuator are mechanical actuators.

Device of the embodiment 25. according to any one of embodiment 22-24, wherein needle seal pass through solid relative to nozzle Fixed washer, wherein washer sealing feeder channel.

Device of the embodiment 26. according to any one of embodiment 1-25, wherein the feeding system include one or Multiple heaters for melting the material.

Device of the embodiment 27. according to embodiment 26 passes wherein the feeding system includes one or more temperature Sensor, the temperature sensor be used to detect the temperature of melted material.

Device of the embodiment 28. according to embodiment 27, wherein one or more of temperature sensors are connected to one A computer system, the temperature which reports in response to one or more of temperature sensors, to control State one or more heaters.

Device of the embodiment 29. according to any one of embodiment 1-28, the wherein tapering point of needle seal or nozzle Cone-shaped inner surface includes flexible liner or bushing.

Equipment of the embodiment 30. according to any one of embodiment 1-29, further includes computer system, the computer System includes one or more processors and computer-readable memory, wherein the computer system be used to set described in control It is standby.

Equipment of the embodiment 31. according to embodiment 31, wherein the computer-readable memory includes for using The equipment carrys out the instruction of printed product.

Device of the embodiment 32. according to embodiment 30 or 31, wherein computer-readable memory include for responding The pressure detected by pressure sensor controls the instruction of the pressure of material.

Equipment of the embodiment 33. according to any one of embodiment 30-32, wherein the computer-readable memory packet It includes and controls the instruction of the temperature of the material for responding the temperature detected by the temperature sensor.

34. increasing material manufacturing system of embodiment includes multiple devices according to any one of embodiment 1-29, wherein often A feeding system is switched configured with control.

System of the embodiment 35. according to embodiment 34 comprising be mounted with the first device and loading of the first material There is the second device of the second material, wherein the first material and the second material are different.

System of the embodiment 36. according to embodiment 34 or 35, further includes computer system, the computer system packet One or more processors and computer-readable memory are included, wherein the computer system is configured as controlling the system.

System of the embodiment 37. according to embodiment 36, wherein the computer-readable memory includes for using The system carrys out the instruction of printed product.

System of the embodiment 38. according to embodiment 36 or 37, wherein computer-readable memory include for responding Pressure that pressure sensor in corresponding feeding system detects controls the instruction of the pressure of the material in each feeding system.

System of the embodiment 39. according to any one of embodiment 36-38, wherein computer-readable memory include using The temperature of the material in each feeding system is controlled in the temperature that temperature sensor of the response in corresponding feeding system detects The instruction of degree.

The method that embodiment 40. manufactures product by increasing material manufacturing, including：

Melting and pressurised material；

Material is set to flow through the extrusion of the nozzle including cone-shaped inner surface；

Monitor the material pressure in nozzle or near nozzle；

The tapering point for making needle seal is engaged with the cone-shaped inner surface of nozzle, to close extrusion and prevent the stream of melted material It is dynamic；With

The tapered end of pumpback needle seal, the flowing for passing through extrusion to restorer.

Method of the embodiment 41. according to embodiment 40, including receive the instruction for manufacturing product.

The method that embodiment 42. produces pharmaceutical dosage form by increasing material manufacturing, including：

It melts and medicinal materials of pressurizeing；

Monitor nozzle in or nozzle nearby material pressure；

Material is set to flow through the extrusion of the nozzle including cone-shaped inner surface；

The tapering point for making needle seal is engaged with the cone-shaped inner surface of nozzle, to close extrusion and prevent the stream of melted material It is dynamic；With

The tapered end of pumpback needle seal, the flowing for passing through extrusion to restorer.

Method of the embodiment 43. according to embodiment 42, wherein the medicinal materials include drug.

Method of the embodiment 44. according to embodiment 43, wherein pharmaceutical dosage form have desired drug release patterns.

Method of the embodiment 45. according to any one of embodiment 42-44, including receive for manufacturing pharmaceutical dosage form Instruction.

Method of the embodiment 46. according to any one of embodiment 40-45, the pressure of material keeps close wherein in nozzle Like constant.

Method of the embodiment 47. according to any one of embodiment 40-46, including pressure based on monitoring use feedback System controls the pressure of material.

Method of the embodiment 48. according to any one of embodiment 40-47, wherein the material is non-wire rod.

Method of the embodiment 49. according to any one of embodiment 40-48, wherein contacting the sealing of the material Any part of needle does not have protrusion.

Method of the embodiment 50. according to any one of embodiment 40-49, the temperature of material keeps close wherein in nozzle Like constant.

Method of the embodiment 51. according to any one of embodiment 40-50 includes the temperature of monitoring material.

Method of the embodiment 52. according to embodiment 51 includes being controlled using reponse system based on the temperature monitored The temperature of prepared material.

Method of the embodiment 53. according to any one of embodiment 40-52, the wherein tapering point of needle seal include point Head.

The tapering point of method of the embodiment 54. according to any one of embodiment 40-52, wherein needle seal is butt circle Cone.

Method of the embodiment 55. according to any one of embodiment 40-55, wherein table in the taper of the nozzle The tapering point of the face with the first cone angle and the needle seal is with the second cone angle；And wherein described second cone angle and institute The first cone angle is stated identical or less than first cone angle.

Method of the embodiment 56. according to embodiment 55, wherein second cone angle is about 60 ° or smaller.

Method of the embodiment 57. according to embodiment 55 or 56, wherein second cone angle is about 45 ° or smaller.

Method of the embodiment 58. according to any one of embodiment 55-57, wherein the ratio of the first cone angle and the second cone angle Rate is about 1：1 to about 4：1.

Method of the embodiment 59. according to any one of embodiment 40-58, wherein the extrusion has about 0.1mm To the diameter of about 1mm.

Method of the embodiment 60. according to any one of embodiment 40-59, wherein the tapering point have about 0.2 to The maximum gauge of about 3.0mm.

Method of the embodiment 61. according to any one of embodiment 40-60, wherein the extrusion have diameter and The tapering point has maximum gauge, and the ratio of the diameter of the maximum gauge of the tapering point and the extrusion is about 1:0.8 to about 1:0.1.

Method of the embodiment 62. according to any one of embodiment 40-60, wherein the material has about

100Pas or higher viscosity.

A kind of method that product is produced by increasing material manufacturing of embodiment 63., including：

It melts and first material that pressurizes；

First material is set to flow through the first extrusion of the first jet including cone-shaped inner surface；

The tapered end for making the first needle seal is engaged with the cone-shaped inner surface of first jet, to the first extrusion of closing and is prevented The flowing of first material of melting；

It melts and second of the material that pressurize；With

From the tapering point of the second needle seal of cone-shaped inner surface pumpback of second nozzle, to which the second material begins to flow through the second extrusion Mouthful.

Method of the embodiment 64. according to embodiment 63, including receive the instruction for manufacturing product.

A kind of method that pharmaceutical dosage form is produced by increasing material manufacturing of embodiment 65., including：

First medicinal materials are melted and pressurizeed；

The first medicinal materials are made to flow through the first extrusion of the first jet including cone-shaped inner surface；

The tapered end for making the first needle seal is engaged with the cone-shaped inner surface of first jet, to the first extrusion of closing and is prevented The flowing of first material of melting；

Second medicinal materials are melted and pressurizeed；With

From the tapered end of the second needle seal of cone-shaped inner surface pumpback of second nozzle, thus start that the second medicinal materials is made to flow through Second squeezes out port.

Method of the embodiment 66. according to embodiment 65, wherein first medicinal materials or the second medicinal material Material is corrosion material.

Method of the embodiment 67. according to embodiment 65 or 66, wherein first medicinal materials or second medicine Include drug with material.

Method of the embodiment 68. according to embodiment 67, wherein the pharmaceutical dosage form has desired drug release bent Line.

Method of the embodiment 69. according to any one of embodiment 65-68, including receive for manufacturing pharmaceutical dosage form Instruction.

In method of the embodiment 70. according to any one of embodiment 63-69, including the monitoring first jet or institute State the pressure of first material near first jet；Monitoring second nozzle in or second nozzle nearby the second material pressure Power.

Method of the embodiment 71. according to any one of embodiment 63-70, the first material wherein in first jet The pressure of the second material in pressure or second nozzle keeps approximately constant.

Method of the embodiment 72. according to any one of embodiment 63-71 includes being used instead based on the pressure monitored Feedback system controls the pressure of first material or second material.

Method of the embodiment 73. according to any one of embodiment 63-72, wherein first material or described second Material is non-wire rod.

Method of the embodiment 74. according to any one of embodiment 63-73, wherein contacting the first sealing of the first material Any part of second needle seal of the second material of any part or contact of needle does not have protrusion.

Method of the embodiment 75. according to any one of embodiment 63-74, the first material wherein in first jet Temperature or the second material in second nozzle temperature keep approximately constant.

Method of the embodiment 76. according to any one of embodiment 63-75 includes the temperature or the of the first material of monitoring The temperature of two materials.

Method of the embodiment 77. according to embodiment 76 includes the temperature based on first material monitored, makes The temperature of first material, or the temperature based on the second material monitored are controlled with reponse system, are using feedback It unites to control the temperature of second material.

Method of the embodiment 78. as described in any one of embodiment 63-77, wherein the cone of first needle seal The tapering point of shape end or second needle seal includes sharp tips.

Method of the embodiment 79. as described in any one of embodiment 63-77, wherein the cone of first needle seal The tapering point of shape end or second needle seal is truncated cone.

Method of the embodiment 80. according to any one of embodiment 63-79, wherein：

Tapering point of the cone-shaped inner surface of the first jet with the first cone angle and first needle seal is with the second cone Angle；And wherein described second cone angle is equal to or less than first cone angle；Or

Tapering point of the cone-shaped inner surface of the second nozzle with third cone angle and second needle seal is with the 4th cone Angle；And wherein described 4th cone angle is equal to or less than the third cone angle.

Method of the embodiment 81. according to embodiment 80, wherein about 60 ° of second cone angle or the 4th cone angle or more It is small.

Method of the embodiment 82. according to embodiment 80 or 81, wherein about 45 ° of second cone angle or the 4th cone angle or Smaller.

Method of the embodiment 83. according to any one of embodiment 79-82, wherein first cone angle and described second The ratio of cone angle or the ratio of the third cone angle and the 4th cone angle are about 1：1 to about 4：1.

Method of the embodiment 84. according to any one of embodiment 79-83, wherein first extrusion or described Two extrusions have the diameter of about 0.1mm to about 1mm.

Method of the embodiment 85. according to any one of embodiment 79-84, wherein the tapering point of the first needle seal or The tapering point of two needle seals has about 0.2 to about 3.0mm maximum gauge.

Method of the embodiment 86. according to any one of embodiment 79-85, wherein first material or described second Material has about 100Pas or higher viscosity.

Method of the embodiment 87. as described in any one of embodiment 40-86, wherein the product or pharmaceutical dosage form are in batches Pattern manufactures.

Method of the embodiment 88. as described in any one of embodiment 40-86, the wherein product or the pharmaceutical dosage form are with continuous Pattern manufactures.

Product or pharmaceutical dosage form prepared by method of the embodiment 89. according to any one of embodiment 40-88.

Case 1

The equipment as shown in Fig. 2A -2B and Fig. 5 A-5C, precision, which uses, contains 80.75%VA64, The material of 14.25% triethyl citrate (TEC) and 5% drug, which is loaded into the barrel of device, to be measured.Material is in barrel In be heated to 110 DEG C, 110 DEG C are heated in feeder channel, 135 DEG C are heated in print head.Print head includes a band There is the stainless steel nozzle of 0.4 millimeter of extrusion.Material is forced into 0.5MPa's (± 0.02MPa) using the piston in insertion tube Pressure is responded by pressure controller and is controlled by the pressure that pressure sensor detects.Needle seal is located in open position 2.50 seconds, 3.33 seconds or 5 seconds, and measure the quality of the material squeezed out by extrusion.The results are shown in Table 1.

Table 1

Case 2

The equipment as shown in Fig. 2A -2B and Fig. 5 A-5C, precision use contain 79.68%HPC, 19.92% citric acid three The material of ethyl ester (TEC) and 0.4% drug, which is loaded into the barrel of device, to be measured.Barrel is heated to 90 DEG C, feeder channel 110 DEG C are heated to, print head is heated to 120 DEG C.Print head includes a stainless steel nozzle for carrying 0.3 millimeter of extrusion.Make Material is forced into the pressure of 1.2MPa (± 0.05MPa) with the piston in insertion tube, by pressure controller in response to by pressure The pressure that sensor detects is controlled.Needle seal is located in open position 1.25 seconds, 2.5 seconds or 5 seconds, and measure and pass through The quality for the material that extrusion squeezes out.As a result it is shown in table 2.

Table 2

Case 3

The equipment as shown in Fig. 2A -2B and Fig. 5 A-5C, precision use 100%RSPO is simultaneously loaded into It is measured in the barrel of device.Barrel is heated to 140 DEG C, and feeder channel is heated to 140 DEG C, and print head is heated to 165 DEG C.It beats Print head includes a stainless steel nozzle for carrying 0.3 millimeter of extrusion.Material is forced into using the piston in insertion tube The pressure of 1.2MPa (± 0.05MPa) is controlled by pressure controller in response to the pressure detected by pressure sensor.It is close Envelope needle is located in open position 1.67 seconds, 4 seconds or 7 seconds, and measures the quality of the material squeezed out by extrusion.As a result it is shown in In table 3.

Table 3

Although embodiment of the disclosure has carried out sufficient description by attached drawing, it should be noted that for this field For technical staff, variations and modifications will become obvious.It is such change and modification should be read to include by In the range of the example of the disclosure defined in the appended claims.

Claims (51)

1. it is a kind of by increasing material manufacturing come the device of deposition materials, including：

Feeding system, the feeding system is used to melt and the material that pressurizes, and the feeding system includes being connected to including spray The feeder channel of the print head of mouth, the nozzle include cone-shaped inner surface and the extrusion for printed material；

Pressure sensor, the pressure sensor are used to detect in the feeder channel near the nozzle or the nozzle The pressure of material；With

Control switch comprising the needle seal that can switch in open position and closed position, the needle seal extends through described A part for feeder channel and include tapering point；

The tapering point of the wherein described needle seal engages the cone-shaped inner surface of the nozzle, to be in the needle seal Material is prevented to flow through the nozzle when closed position.

2. the apparatus according to claim 1, wherein the material is non-wire rod.

3. device according to claim 1 or 2, wherein any part of the needle seal and the material is not prominent It rises.

4. device according to any one of claim 1 to 3, wherein the pressure sensor is connected to computer system, Feeding system described in the computer system operation is to add the material in response to the pressure reported by the pressure sensor It is depressed into desired pressure value.

5. according to the device described in any one of claim 1-4, wherein the feeding system includes piston and is connected to described The barrel of feeder channel, and the wherein described piston is operated to control the pressure of the material in the barrel.

6. device according to any one of claim 1 to 5, wherein the tapering point of the needle seal includes tip.

7. device according to any one of claim 1 to 6, wherein the cone-shaped inner surface of the nozzle has the first cone Angle, and the tapering point of the needle seal has the second cone angle；And wherein described second cone angle is identical as first cone angle Or it is less than first cone angle.

8. according to the device described in any one of claim 1-7, wherein when material is squeezed out from described device, the material tool There is about 100Pas or higher viscosity.

9. according to the device described in any one of claim 1-8, wherein the material is melted at about 50 DEG C to about 400 DEG C.

10. according to the device described in any one of claim 1-9, wherein temperature of the material at about 50 DEG C to about 400 DEG C Under from the nozzle squeeze out.

11. according to the device described in any one of claim 1-10, wherein control switch includes actuator, the actuating The needle seal is located in the open position or the closed position by device.

12. according to the devices described in claim 11, wherein the actuator is pneumatic actuator or mechanical actuator.

13. device according to claim 11 or 12, wherein the needle seal is passed through relative to the fixed pad of the nozzle Circle, wherein feeder channel described in the washer sealing.

14. according to the device described in any one of claim 1-13, wherein the feeding system is used for including one or more Melt the heater of the material.

15. device according to claim 14, wherein the feeding system includes for detecting the melted material temperature One or more temperature sensors.

16. device according to claim 15, wherein one or more of temperature sensors are connected in response to by institute It states the temperature of one or more temperature sensors report and controls the computer systems of one or more of heaters.

17. the device according to any one of claim 1 to 16, wherein the tapered end or described of the needle seal The cone-shaped inner surface of nozzle includes flexible liner or bushing.

Further include computer system 18. according to the equipment described in any one of claim 1-17, the computer system includes One or more processors and computer-readable memory, wherein the computer system is configured as controlling the equipment.

19. equipment according to claim 18, wherein the computer-readable memory includes for using the equipment Carry out the instruction of printed product.

20. the device according to claim 18 or 19, wherein the computer-readable memory includes for responding by institute The pressure that pressure sensor detects is stated to control the instruction of the pressure of the material.

21. according to the device described in any one of claim 18-20, wherein the computer-readable memory includes using The instruction of the temperature of the material is controlled in the temperature that response is detected by the temperature sensor.

22. a kind of includes the increasing material manufacturing system of multiple devices according to any one of claim 1-18, wherein each Feeding system is switched configured with control.

23. system according to claim 22, including be mounted with the first device of the first material and be mounted with the second material Second device, wherein first material and second material are different.

24. the system according to claim 22 or 23 further includes computer system, the computer system include one or Multiple processors and computer-readable memory, wherein the computer system is configured as controlling the system.

25. system according to claim 24, wherein the computer-readable memory includes for using the system The instruction of printed product.

26. the system according to claim 24 or 25, wherein the computer-readable memory includes for responding by phase The pressure that the pressure sensor in feeding system detects is answered to control the instruction of the pressure of the material in each feeding system.

27. the system according to any one of claim 24 to 26, wherein the computer-readable memory includes being used for The temperature that is detected by the temperature sensor in the corresponding feeding system is responded to control the material in each feeding system The instruction of the temperature of material.

28. a kind of method that product is produced by increasing material manufacturing, including：

Melting and pressurised material；

Material is set to flow through the extrusion of the nozzle including cone-shaped inner surface；

Monitor the material pressure in nozzle or near nozzle；

The tapering point for making needle seal is engaged with the cone-shaped inner surface of nozzle, to close extrusion and prevent the stream of melted material It is dynamic；With

The tapered end of pumpback needle seal, to which restorer passes through the flowing of extrusion port.

29. according to the method for claim 28, including instruction of the reception for manufacturing the product.

30. a kind of method that pharmaceutical dosage form is produced by increasing material manufacturing, including：

Medicinal materials are melted and pressurizeed；

Monitor the material pressure in nozzle or near nozzle；

Material is set to flow through the extrusion of the nozzle including cone-shaped inner surface；

The tapering point for making needle seal is engaged with the cone-shaped inner surface of nozzle, to close extrusion and prevent the stream of melted material It is dynamic；With

The tapered end of pumpback needle seal, to which restorer passes through the flowing of extrusion port.

31. according to the method for claim 30, wherein the medicinal materials include drug.

32. according to the method for claim 31, wherein the pharmaceutical dosage form has desired drug release patterns.

33. according to the method described in any one of claim 30-32, including receiving the finger for manufacturing the pharmaceutical dosage form It enables.

34. according to the method described in any one of claim 28-33, include based on the pressure monitored using reponse system come Control the pressure of the material.

35. according to the method described in any one of claim 28-34, wherein the needle seal contacts any portion of the material Divide no protrusion.

36. including according to the method for claim 35, controlling the material using reponse system based on the temperature monitored The temperature of material.

37. according to the method described in any one of claim 28-36, wherein the cone-shaped inner surface of the nozzle has the The tapering point of one cone angle and the needle seal has the second cone angle；And wherein described second cone angle is equal to or less than institute State the first cone angle.

38. a kind of method that product is produced by increasing material manufacturing, including：

It melts and first material that pressurizes；

First material is set to flow through the first extrusion of the first jet including cone-shaped inner surface；

The tapered end for making the first needle seal is engaged with the cone-shaped inner surface of first jet, to the first extrusion of closing and is prevented The flowing of first material of melting；

It melts and second of the material that pressurize；With

From the tapering point of the second needle seal of cone-shaped inner surface pumpback of second nozzle, thus starting, which makes the second material flow through second, squeezes Outlet.

39. according to the method for claim 38, including instruction of the reception for manufacturing the product.

40. a kind of method that pharmaceutical dosage form is produced by increasing material manufacturing, including：

First medicinal materials are melted and pressurizeed；

The first medicinal materials are made to flow through the first extrusion of the first jet including cone-shaped inner surface；

The tapering point for making the first needle seal is engaged with the cone-shaped inner surface of first jet, to the first extrusion of sealing and is prevented molten The flowing of the first material melted；

Second medicinal materials are melted and pressurizeed；With

From the tapered end of the second needle seal of cone-shaped inner surface pumpback of second nozzle, thus start that the second medicinal materials is made to flow through Second extrusion.

41. according to the method for claim 40, wherein first medicinal materials or second medicinal materials are corrosions Material.

42. the method according to claim 40 or 41, wherein first medicinal materials or the second medicinal materials packet Drug containing.

43. according to the method for claim 42, wherein the pharmaceutical dosage form has desired drug release patterns.

44. according to the method described in any one of claim 40-43, including receiving the finger for manufacturing the pharmaceutical dosage form It enables.

45. according to the method described in any one of claim 38-44, include based on the pressure monitored using reponse system come Control the pressure of first material or second material.

46. according to the method described in any one of claim 38-45, wherein first needle seal with first material Any part of contact or second needle seal do not have protrusion with any part of second material.

Include the temperature based on first material monitored 47. according to the method described in any one of claim 38-46 Control the temperature of first material using reponse system, or the temperature based on the second material of monitoring using reponse system come Control the temperature of second material.

48. according to the method described in any one of claim 38-47, wherein：

Tapering point of the cone-shaped inner surface of the first jet with the first cone angle and first needle seal is with the second cone Angle；And wherein described second cone angle is equal to or less than first cone angle；Or

Tapering point of the cone-shaped inner surface of the second nozzle with third cone angle and second needle seal is with the 4th cone Angle；And wherein described 4th cone angle is equal to or less than the third cone angle.

49. according to the method described in any one of claim 38-48, wherein the product or the pharmaceutical dosage form are with mould in batches Formula manufactures.

50. according to the method described in any one of claim 38-48, wherein the product or the pharmaceutical dosage form are with the progressive die Formula manufactures.

51. the product or pharmaceutical dosage form that are prepared according to the method for any one of claim 28-50.